The global importance of rare variants in tumorigenesis has been addressed by some pan-cancer analysis, revealing significant enrichments in protein-truncating variants affecting genes such as ATM, BRCA1/2, BRIP1, and MSH6. Germline variants can influence treatment response and contribute to the development of treatment-related second neoplasms, especially in childhood leukemia. The gene discussed is MSH6; the disease is childhood leukemia.